The Ret proto-oncogene encodes a receptor tyrosine kinase (RTK) which has diverse roles in mammalian development and disease. Loss-of-function RET mutations are associated with Hirschsprung?s disease, which results from defects in the formation of the enteric nervous system (ENS) from neural crest progenitors, while gain-of-function mutations can cause cancers including Multiple Endocrine Neoplasia. Despite clear evidence implicating RET and its ligands in these disease processes, and extensive studies of the downstream signaling pathways that can potentially be activated by RET, the specific intracellular pathways through which RET, together with other signaling systems, directs the normal and abnormal development of the ENS remains to be elucidated. Here we focus on the mechanism by which RET regulates the proliferation, migration, survival and differentiation of neural crest cells in the developing gut. Our approach makes extensive use of knock-in mouse models, as well as organ and cell culture systems, to examine the in vivo functions of the genetically modified RET receptors in enteric neural crest cells. The questions we address are (1) the possible role of RET as a pro-apoptotic factor, which can promote cell death through a mechanism involving cleavage of the RET intracellular domain, and the importance of this function in normal embryogenesis and in tumor suppression in the adult animal; (2) the mechanisms by which RET and the endothelin receptor-beta signaling pathways interact to control the normal histogenesis of the ENS, and the possible role of PKA and other serine/threonine kinases in these interactions; and (3) the molecular basis for the distinct signaling abilities of the two major RET isoforms, RET9 and RET51, which differ in their capacity to support normal ENS development. These studies will not only advance our understanding of how this RTK functions during development of the enteric nervous system, but will provide insight into the downstream signaling pathways that might be targets for intervention in the treatment of Ret-related cancers.